Artemisinin-based combination therapy for ... - The Cochrane Library

B A C K G R O U N D
Malaria is a disease of global public health importance. Its social
and economic burden is a major obstacle to human development
in many of the world’s poorest countries. In heavily affected countries,
malaria alone accounts for as much as 40% of public health
expenditure, 30% to 50% of hospital admissions, and up to 60%
of outpatient visits (WHO 2007). It has an annual incidence of
approximately 250 million episodes and is the cause of more than
a million deaths, most of them in infants, young children, and
pregnant women (WHO 2008b).
Malaria is transmitted from person to person by the bite of
mosquitoes infected with the protozoan parasite Plasmodium. Four
Plasmodium species are capable of causing malaria in humans: P.
falciparum, P. vivax, P. malariae, and P. ovale. Of these P. falciparum
is responsible for over 90% of cases and almost all of the malaria
deaths worldwide (WHO 2008b). P. vivax is also common and
often presents as a co-infection with P. falciparum in a single illness
(Mayxay 2004). Uncomplicated malaria is the mild form of the
disease which presents as a febrile illness with headache, tiredness,
muscle pains, abdominal pains, rigors (severe shivering), and nausea
and vomiting. If left untreated P. falciparum malaria can rapidly
develop into severe malaria with anaemia (low haemoglobin in
the blood), hypoglycaemia (low blood sugar), renal failure (kidney
failure), pulmonary oedema (fluid in the lungs), convulsions
(fitting), coma, and eventually death (WHO 2006). A clinical diagnosis
of malaria can be confirmed by detection of the malaria
parasite in the patient’s blood. This has traditionally been done by
light microscopy but increasingly rapid diagnostic tests are being
used.
Resistance of P. falciparum to the traditional antimalarial drugs
(such as chloroquine, sulfadoxine-pyrimethamine, amodiaquine,
and mefloquine) is a growing problem and is thought to have
contributed to increased malaria mortality in recent years (WHO
2006). Chloroquine resistance has now been documented in all
regions except Central America and the Caribbean. There is highlevel
resistance to sulfadoxine-pyrimethamine throughout South
East Asia and increasingly in Africa. Mefloquine resistance is common
in the border areas of Cambodia, Myanmar, and Thailand,
but uncommon elsewhere. Resistance of P. vivax to sulfadoxinepyrimethamine
is also increasing, and chloroquine resistance has
been reported in some parts of Asia and Oceania (WHO 2006).
Artemisinin-based antimalarials
Artemisinin and its derivatives (such as artesunate, artemether, and
dihydroartemisinin) are antimalarial drugs with a unique structure
and mode of action. The first published report of clinical trials
appeared in the Chinese Medical Journal in 1979 (Qinghaosu
1979). Until recently there had been no reported resistance to the
artemisinin derivatives; however the possibility of emerging resis-
Artemisinin-based combination therapy for treating uncomplicated malaria (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
tance, on the Thai-Cambodian border, is currently being investigated
(WHO 2008a).
Artemisinin derivatives have been shown to produce faster relief
of clinical symptoms and faster clearance of parasites from
the blood than other antimalarial drugs (McIntosh 1999; Adjuik
2004; WHO 2006). When used as monotherapy, the short halflife
of the artemisinin derivatives (and rapid elimination from
the blood) means that patients must take the drug for at least
seven days (Meshnick 1996; Adjuik 2004). Failure to complete the
course, due to the rapid improvement in clinical symptoms, can
lead to high levels of treatment failure even in the absence of drug
resistance. Artemisinin derivatives are therefore usually given with
another longer-acting drug, with a different mode of action, in a
combination known as artemisinin-based combination therapy or
ACT. These combinations can then be taken for shorter durations
than artemisinin alone (White 1999; WHO 2006).
The artemisinin derivatives also reduce the development of gametocytes
(the sexual form of the malaria parasite that is capable of infecting
mosquitoes) and consequently the carriage of gametocytes
in the peripheral blood (Price 1996; Targett 2001). This reduction
in infectivity has the potential to reduce the post-treatment
transmission of malaria (particularly in areas of low or seasonal
transmission), which may have significant public health benefits (
WHO 2006).
Artemisinin and its derivatives are generally reported as being safe
and well tolerated, and the safety profile of ACTs may be largely determined
by the partner drug (WHO 2006; Nosten 2007). Studies
of artemisinin derivatives in animals have reported significant
neurotoxicity (brain damage), but this has not been seen in human
studies (Price 1999). Animal studies have also shown adverse
effects on the early development of the fetus, but the artemisinin
derivatives have not been fully evaluated during early pregnancy
in humans (Nosten 2007). Other reported adverse events include
gastrointestinal (GI) disturbance (stomach upset), dizziness, tinnitus
(ringing in the ears), neutropenia (low levels of white blood
cells), elevated liver enzymes (a marker for liver damage), and electrocardiographic
(ECG) abnormalities (changes in cardiac conduction).
Most studies however, have found no evidence of ECG
changes, and only non-significant changes in liver enzymes (WHO
2006; Nosten 2007). The incidence of type 1 hypersensitivity (allergic)
reactions is reported to be approximately 1 in 3000 patients
(Nosten 2007).
Assessing antimalarial efficacy
The World Health Organization (WHO) recommends that firstline
antimalarials should have a treatment failure rate of less than
10%, and failure rates higher than this should trigger a change in
treatment policy (WHO 2006). Treatment failure can be classified
as:
Early treatment failure:
3